Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells

Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis.

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells

Multiple Translocation of the AVR-Pita Effector Gene among Chromosomes of the Rice Blast Fungus Magnaporthe oryzae and Related Species

Magnaporthe oryzae is the causal agent of rice blast disease, a devastating problem worldwide. This fungus has caused breakdown of resistance conferred by newly developed commercial cultivars. To address how the rice blast fungus adapts itself to new resistance genes so quickly, we examined chromosomal locations of AVR-Pita, a subtelomeric gene family corresponding to the Pita resistance gene, in various isolates of M. oryzae (including wheat and millet pathogens) and its related species. We found that AVR-Pita (AVR-Pita1 and AVR-Pita2) is highly variable in its genome location, occurring in chromosomes 1, 3, 4, 5, 6, 7, and supernumerary chromosomes, particularly in rice-infecting isolates. When expressed in M. oryzae, most of the AVR-Pita homologs could elicit Pita-mediated resistance, even those from non-rice isolates. AVR-Pita was flanked by a retrotransposon, which presumably contributed to its multiple translocation across the genome. On the other hand, family member AVR-Pita3, which lacks avirulence activity, was stably located on chromosome 7 in a vast majority of isolates. These results suggest that the diversification in genome location of AVR-Pita in the rice isolates is a consequence of recognition by Pita in rice. We propose a model that the multiple translocation of AVR-Pita may be associated with its frequent loss and recovery mediated by its transfer among individuals in asexual populations. This model implies that the high mobility of AVR-Pita is a key mechanism accounting for the rapid adaptation toward Pita. Dynamic adaptation of some fungal plant pathogens may be achieved by deletion and recovery of avirulence genes using a population as a unit of adaptation

Fitness cost of virulence differs between the AvrLm1 and AvrLm4 loci in Leptosphaeria maculans (phoma stem canker of oilseed rape)

“The original publication is available at www.springerlink.com” Copyright Springer [Full text of this article is not available in the UHRA]To investigate whether the reported fitness cost of virulence at the AvrLm4 locus in Leptosphaeria maculans is common to other loci, near-isogenic (NI) isolates differing at AvrLm1 locus were produced in vitro. Fitness of virulent (avrLm1) or avirulent (AvrLm1) isolates on Brassica napus without the corresponding R (resistance) gene Rlm1 was investigated in controlled environment (CE) and field experiments. Results indicate that there is a measurable fitness cost for avrLm1 compared to AvrLm1 isolates in terms of number of lesions, size of lesions, distance grown through leaf tissue towards the petiole in CE experiments and systemic growth from leaf lesions to stems in field experiments. There were differences in fitness cost between the AvrLm1 and AvrLm4 loci. There was a cultivar effect on fitness cost of virulence at the AvrLm1 locus but not at the AvrLm4 locus. In CE experiments, the optimal temperature for leaf infection was greater for AvrLm4 isolates than for AvrLm1 isolates. Field experiment results suggest that on the same host AvrLm4 isolates are more fit than AvrLm1 isolates in warmer seasons. The fitness cost at the AvrLm4 locus was generally greater than at the AvrLm1 locus, suggesting that the corresponding R gene Rlm4 may be more suitable than Rlm1 for redeployment in commercial cultivars after an interval of a few years.Peer reviewe

MNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression.

KRAS-mutant colorectal cancers (CRC) are resistant to therapeutics, presenting a significant problem for ~40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant CRC. Using Kras-mutant mouse models and mouse- and patient-derived organoids we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of CRCs have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC-dependent co-targeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population who may benefit from its clinical application

Control of foliar diseases in barley:towards an integrated approach

Barley is one of the world's most important crops providing food and related products for millions of people. Diseases continue to pose a serious threat to barley production, despite the use of fungicides and resistant varieties, highlighting the impact of fungicide resistance and the breakdown of host plant resistance on the efficacy of control measures. This paper reviews progress towards an integrated approach for disease management in barley in which new methods may be combined with existing measures to improve the efficacy of control in the long-term. Advances have been made in genetic mapping of resistance (R) genes and in identifying novel sources of genes in wild barley populations and land races. Marker assisted selection techniques are being used to pyramid R genes to increase the durability of resistance. Elicitors to induce host resistance used in combination with fungicides can provide effective disease control in the field and could delay the evolution of fungicide insensitivity. Traits that may contribute to disease tolerance and escape have been identified and the extent of genetic variation within barley germplasm is being determined. Tools are being developed to integrate the above methods via an assessment of the risk of economic injury occurring from disease to guide decisions on the requirement for fungicide treatment. Barriers exist to the adoption of integrated management approaches from growers and end-users further down the supply chain (e. g. acceptance of variety mixtures) and policy incentives from government may be required for it to be taken up in practice. © 2012 KNPV